MHC complexes and uses thereof

Abstract

The present invention relates to novel complexes of major histocompability complex (MHC) molecules and uses of such complexes. In particular, the invention relates to MHC fusion complexes that contain a MHC molecule with a peptide-binding groove and a presenting peptide covalently linked to the MHC protein. Fusion complexes of the invention are useful for a variety of applications including in vitro screens for identification and isolation of peptides that modulate activity of selected T cells, including peptides that are T cell receptor antagonists and partial agonists, methods of suppressing an immune response of a mammal and methods for inducing an immune response in a mammal.

1. A multivalent MHC fusion complex comprising two or more linked MHC fusion complexes,
 wherein each MHC fusion complex comprises a MHC class II molecule that contains a peptide-biding groove, an antigenic or antagonistic presenting peptide covalently linked to an N-terminus of the MHC molecule and effectively positioned in the peptide-binding groove, and a linker sequence interposed between the presenting peptide and the MHC molecule, the fusion complex being capable of increasing or decreasing T cell proliferation or activity, wherein the MHC fusion complex are genetically modified to include a terminal amino acid residue(s) with chemically reactive side chains and the reactive side chains are used to chemically cross-link the MHC fusion complexes. 
 
     
     
       2. The multivalent MHC fusion complex of  claim 1 , wherein the MHC fusion complex does not contain the transmembrane and cytoplasmic domains of the MHC molecule and is linked to an immunoglobulin. 
     
     
       3. The multivalent MHC fusion complex of  claim 2 , wherein the immunoglobulin is IgG, IgM or Fab′ 2 . 
     
     
       4. The multivalent MHC fusion complex of  claim 1 , wherein two or more of the MHC fusion complexes are chemically cross-linked together or to a suitable particle. 
     
     
       5. The multivalent MHC fusion complex of  claim 1  wherein the C terminus of the β chain of MHC fusion complex is genetically modified to include amino acid residue(s) with chemically reactive side chains. 
     
     
       6. The multivalent MHC fusion complex of  claim 1  wherein two or more of the MHC fusion complexes are chemically cross-linked to a dendrimer particle. 
     
     
       7. The multivalent MHC fusion complex of  claim 1 , wherein each MHC fusion complex therein is the same. 
     
     
       8. A multivalent MHC fusion complex comprising two or more linked MHC fusion complexes,
 wherein each MHC fusion complex comprises a MHC class II molecule that contains a peptide-biding groove, an antigenic or antagonistic presenting peptide covalently linked to an N-terminus of the MHC molecule and effectively positioned in the peptide-binding groove, and a linker sequence interposed between the presenting peptide and the MHC molecule, the fusion complex being capable of increasing or decreasing T cell proliferation or activity, wherein the MHC fusion complex are genetically modified to include a terminal amino acid residue(s) with chemically reactive side chains and the reactive side chains are used to chemically cross-link the MHC fusion complexes and further wherein each MHC fusion complex therein is the same. 
 
     
     
       9. A multivalent MHC fusion complex comprising two or more linked MHC fusion complexes,
 wherein each MHC fusion complex comprises a MHC class II molecule that contains a peptide-biding groove, an antigenic or antagonistic presenting peptide covalently linked to an N-terminus of the MHC molecule and effectively positioned in the peptide-binding groove, and a linker sequence interposed between the presenting peptide and the MHC molecule, the fusion complex being capable of increasing or decreasing T cell proliferation or activity, wherein the MHC fusion complex are genetically modified to include a terminal amino acid residue(s) with chemically reactive side chains and the reactive side chains are used to chemically cross-link the MHC fusion complexes and further wherein the amino acid is a Cys or His residue. 
 
     
     
       10. A multivalent MHC fusion complex comprising two or more linked MHC fusion complexes,
 wherein each MHC fusion complex comprises a MHC class II molecule that contains a peptide-biding groove, an antigenic or antagonistic presenting peptide covalently linked to an N-terminus of the MHC molecule and effectively positioned in the peptide-binding groove, and a linker sequence interposed between the presenting peptide and the MHC molecule, the fusion complex being capable of increasing or decreasing T cell proliferation or activity, wherein the MHC fusion complex are genetically modified to include a terminal amino acid residue(s) with chemically reactive side chains and the reactive side chains are used to chemically cross-link the MHC fusion complexes and further wherein wherein the C terminus of the β chain of MHC fusion complex is genetically modified to include amino acid residue(s) with chemically reactive side chains and the amino acid is a Cys or His residue.